medwireNews: Japanese researchers have identified a dose of the peripherally acting µ-opioid receptor antagonist (PAMORA) naldemedine suitable for testing in a phase III study of opioid-induced constipation in patients with cancer.

Nobuyuki Katakami, from the Institute of Biomedical Research and Innovation in Kobe, and co-workers report that an oral 0.2 mg once daily dose of naldemedine, given for 14 days, is effective and well tolerated in adults receiving a stable dose of opioid analgesics for at least 2 weeks.

The 227 patients with cancer participating in the phase IIb trial had at least one symptom of constipation and had achieved no more than five spontaneous bowel movements (SBMs) in the past 14 days despite using laxatives, the team explains in the Journal of Clinical Oncology.

The primary endpoint of improvement in the frequency of SBMs was significantly greater in patients given daily naldemedine at a dose of 0.1 mg (n=55), 0.2 mg (n=58) or 0.4 mg (n=56) than in placebo-treated controls (n=56). The least-squares mean change from baseline were 3.43, 4.75 and 7.29 versus 1.50, respectively, demonstrating a dose–response effect.

Patients given naldemedine 0.2 mg and 0.4 mg – but not 0.1 mg – also had a significantly greater change in SBM frequency without straining than those given placebo, while there was a significant improvement in the frequency of SBM with the feeling of complete evacuation for all doses of the PAMORA.

The rate of response to naldemedine increased from 56.4% of patients given 0.1 mg dose to 77.6% of patients given 0.2 mg and 82.1% for those given the 0.4 mg dose, whereas just 37.5% of the placebo-treated patients responded to treatment.

However, 66.1%, 67.2% and 78.6% of patients given the 0.1, 0.2 and 0.4 mg doses of naldemedine experienced treatment-emergent adverse events compared with 51.8% of controls.

Diarrhoea was the most common side effect but the majority of these cases were mild, defined as three or fewer episodes per day. And the researchers explain that the “incidence of diarrhea may be elevated because […] patient-reported BMs with a score of 7 (on the Bristol Stool Form Scale) were automatically regarded as an [adverse event] of diarrhea, regardless of an actual patient complaint of diarrhea.”

Moreover, naldemedine treatment did not significantly impact pain management, as measured by the Numerical Rating Scale and Clinical Opiate Withdrawal Scale. Nor did treatment lead to a change in opioid doses or use of rescue opioid doses in the patients.

The investigators note that the 0.2 mg dose showed significant efficacy in all assessments without a substantial increase in the rate of adverse events compared with placebo. “A once-daily dose of oral naldemedine 0.2 mg was, therefore, considered to be the dose with the best risk and benefit balance for future clinical trials”, they write.

“To our knowledge, this study is the first to successfully prospectively demonstrate the feasibility of using an oral PAMORA to alleviate symptoms of [opioid-induced constipation] specifically in patients with cancer”, Nobuyuki Katakami et al say.

Naldemedine reduced opioid-induced constipation in a “significant, clinically meaningful, and generally well-tolerated manner, without abrogation of the centrally mediated analgesic effects of opioids”, they summarise.

The team therefore concludes: “Naldemedine 0.2 mg was chosen as the dose for the phase III studies of naldemedine in patients with cancer and [opioid-induced constipation].